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. 2024 Feb 2;18(1):12.
doi: 10.1186/s40246-024-00576-x.

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk

Pelin Ünal  1 , Ye Lu  1 , Bas Bueno-de-Mesquita  2 , Casper H J van Eijck  3 , Renata Talar-Wojnarowska  4 , Andrea Szentesi  5 , Maria Gazouli  6 , Edita Kreivenaite  7 , Francesca Tavano  8 , Ewa Małecka-Wojciesko  4 , Bálint Erőss  5   9   10 , Martin Oliverius  11 , Stefania Bunduc  9   10   12 , Mateus Nóbrega Aoki  13 , Ludmila Vodickova  14   15   16 , Ugo Boggi  17 , Matteo Giaccherini  18 , Jurate Kondrackiene  7 , Roger Chammas  19 , Orazio Palmieri  8 , George E Theodoropoulos  20 , Maarten F Bijlsma  21   22 , Daniela Basso  23 , Beatrice Mohelnikova-Duchonova  24 , Pavel Soucek  14 , Jakob R Izbicki  25 , Vytautas Kiudelis  7 , Giuseppe Vanella  26   27 , Paolo Giorgio Arcidiacono  26 , Barbara Włodarczyk  4 , Thilo Hackert  28 , Ben Schöttker  29   30 , Faik G Uzunoglu  25 , Franco Bambi  31 , Mara Goetz  25 , Viktor Hlavac  14 , Hermann Brenner  29   30   32   33 , Francesco Perri  8 , Silvia Carrara  34 , Stefano Landi  18 , Péter Hegyi  5   35   9   10 , Frederike Dijk  36 , Evaristo Maiello  37 , Giovanni Capretti  38   39 , Sabrina Gloria Giulia Testoni  26 , Maria Chiara Petrone  26 , Hannah Stocker  29   30 , Stefano Ermini  31 , Livia Archibugi  26   27 , Manuel Gentiluomo  18 , Giulia Martina Cavestro  40 , Raffaele Pezzilli  41 , Gregorio Di Franco  42 , Anna Caterina Milanetto  43 , Cosimo Sperti  43 , John P Neoptolemos  28 , Luca Morelli  42 , Klara Vokacova  15   16 , Claudio Pasquali  43 , Rita T Lawlor  44 , Francesca Bazzocchi  45 , Juozas Kupcinskas  7 , Gabriele Capurso  26   27 , Daniele Campa  18 , Federico Canzian  46
Affiliations

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk

Pelin Ünal et al. Hum Genomics. .

Abstract

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

Keywords: Association study; Enhancer; Pancreatic cancer; Single nucleotide polymorphism; Transcription factor binding site.

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Conflict of interest statement

MFB has received research funding from Celgene, Frame Therapeutics and Lead Pharma and has acted as a consultant to Servier. Other coauthors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Summary of the variant selection workflow
Fig. 2
Fig. 2
Summary of overall meta-analysis results for the four study-wise significant variants
Fig. 3
Fig. 3
a Genomic location of the SNP rs2472632. b CCDC34 gene expression in pancreas tissue from normal vs Pancreatic Adenocarcinoma patients in TNMplot database. c Violin plot of LGR4—rs2472632 sQTL analysis results in GTEx database. d Violin plot of LIN7C-rs2472632 eQTL analysis in GTEx database
See this image and copyright information in PMC

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